Site-Selective Late-Stage Aromatic [18F]Fluorination via Aryl Sulfonium Salts

Article abstract of DOI:10.1002/anie.201912567

Site-selective functionalization of C?H bonds in small complex molecules is a long-standing challenge in organic chemistry. Herein, we report a broadly applicable and site-selective aromatic C?H dibenzothiophenylation reaction. The conceptual advantage of this transformation is further demonstrated through the two-step C?H [¹⁸F]fluorination of a series of marketed small-molecule drugs.

Full text of DOI:10.1002/anie.201912567

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Site-selective Late-Stage Aromatic 18F-Fluorination via Aryl
Sulfonium Salts
Authors: Tobias Ritter, Peng Xu, Da Zhao, Florian Berger, Aboubakr
Hamad, Jens Rickmeier, Roland Petzold, Mykhailo
Kondratiuk, and Kostiantyn Bohdan
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201912567
Angew. Chem. 10.1002/ange.201912567
Link to VoR: http://dx.doi.org/10.1002/anie.201912567
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Angewandte Chemie International Edition
10.1002/anie.201912567
COMMUNICATION
1
8
Site-selective Late-Stage Aromatic F-Fluorination via Aryl
Sulfonium Salts
‡
‡
Peng Xu , Da Zhao , Florian Berger, Aboubakr Hamad, Jens Rickmeier, Roland Petzold, Mykhailo
Kondratiuk, Kostiantyn Bohdan, and Tobias Ritter*
Abstract: Site-selective functionalization of C–H bonds in small
every direct C–H functionalization reaction, especially for PET
complex molecules is a long-standing challenge in organic chemistry. tracer synthesis because even small quantities of constitutional
5
Herein, we report a broadly-applicable and site-selective aromatic
C–H dibenzothiophenylation reaction. The conceptual advantage of
this transformation is further demonstrated through the two-step C–H
isomers must be separated (Scheme 1b). There are only few
highly regioselective arene C–H functionalization reactions, and
all of them either require suitable substitution patterns,
or afford functional groups that are not
suitable for F fluorination. Here we report a highly selective
6
a,d
18
6b,c
F-fluorination of a series of marketed small-molecule drugs.
directing groups,
18
6e
and late-stage C–H functionalization to afford aryl
Over the past ten years, several promising new methods for
1
8
1
8
dibenzothiophenium salts, which can be converted to [ F]Ar–F
in a straightforward nucleophilic aromatic substitution reaction
simply by adding fluoride (Scheme 1c). The C–H
dibenzothiophenylation reaction developed herein can proceed
in high selectivity for both small complex molecules and simple
monosubstituted arenes to afford aryl dibenzothiophenium salts.
Given the high selectivity and the operational simplicity, the two-
the introduction of the F nucleus into small molecules have
been disclosed, with the aim of impacting clinical care and drug
1
8
1,2
discovery through F positron-emission tomography (PET).
1
8
step protocol to quickly access [ F]Ar–F by arene C–H
18
functionalization bodes well to accelerate F PET development.
1
8
Scheme 1. Strategies for aromatic C– F bond formation.
Yet, the implementation and translation to hospital settings is
challenging, if the fluorination reactions are operationally
3
,4
complex. Unfortunately, introduction of conventional leaving
groups that can directly provide aryl fluorides upon reaction with
fluoride cannot currently be accomplished at a late-stage, so the
requirement of de-novo syntheses slows down PET tracer
development (Scheme 1a). Direct C–H fluorination in this regard
is promising but selectivity becomes a substantial concern in
Scheme 2. Synthesis and fluorination of aryl sulfonium salts (TTO
=
thianthrene S-oxide; DBTO = dibenzothiophene S-oxide; B-DBTO = 3,7-di-
tert-butyldibenzothiophene
S-oxide;
M-DBTO
=
2,8-
dimethoxydibenzothiophene S-oxide).
[
a]
Dr. P. Xu, Dr. D. Zhao, Dr. F. Berger, A. Hamad, Dr. J. Rickmeier, R.
Petzold, M. Kondratiuk, K. Bohdan, and Prof. Dr. T. Ritter.
Max-Planck-Institut für Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr (Germany)
E-mail: ritter@mpi-muelheim.mpg.de
18
Some of the modern F fluorination reactions are starting to
1
8
have an impact on the synthesis of structurally complex F-
labeled small molecules that cannot be made by conventional
nucleophilic aromatic substitution. Most notably, practical F-
fluorodemetallation reactions mediated by copper that proceed
on a large variety of small molecules have been developed by
‡
7
18
[
]
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
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Angewandte Chemie International Edition
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COMMUNICATION
7
c
7f,h
7d
Gouverneur as well as Sanford and Scott , and Neumaier .
fluorination is desirable, but control of regioselectivity is
challenging.
7g,i
Our group reported deoxyfluorination reactions that in addition
can also functionalize small peptides. Sanford and Scott
described a Cu-mediated, two-step F-fluorination of electron-
rich arenes via hypervalent iodine compounds. Nicewicz and Li
have developed a promising C–H to C– F fluorination reaction
that does not require coordination directing groups, enabled by
laser-photoredox catalysis.
groups for F-18 introduction can currently be introduced
7
l
18
Aryl sulfonium salts are good precursors for F-labeling of
1
8
8
7
j
arenes. Årstad demonstrated that dibenzothiophene sulfonium
1
8
salts can be efficiently converted to F-labeled arenes for
electron-poor and -neutral substrates including several valuable
1
8
8d
PET tracers. However, previous methods for the preparation of
aryl sulfonium salts often require aryl Grignard reagents, multiple
step syntheses from aryl halides or strong acids as co-solvents,
none of which are suitable for site-selective late-stage
5d
None of the useful functional
1
8
selectively in a late-stage in a general sense. Direct F-
Table 1. Site-selective aromatic C–H dibenzothiophenylation.
(
a) Reaction condition A: 0.500 mmol arene, 2.00 to 4.00 equiv. triflic acid (HOTf), 3.00 equiv. trifluoroacetic anhydride (TFAA) and 1.50 to 2.00 equiv. DBTO or B-
DBTO in MeCN (2.0 mL, c = 0.25 M), –40 °C to 25 °C. (b) Reaction condition B: 0.500 mmol arene, 1.50 to 2.00 equiv. DBTO, B-DBTO or M-DBTO in DCM (2.0
mL, c = 0.25 M), 1.50 to 2.00 equiv. triflic anhydride (Tf O), –40 °C to 25 °C. (c) 3.00 equiv. methanesulfonic anhydride instead of Tf O, and reaction performed at
2
2
0
°C to 25 °C. (d) 2.00 equiv. K
2
CO
3
was added, and reaction performed at –78 °C to 25 °C.
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Angewandte Chemie International Edition
10.1002/anie.201912567
COMMUNICATION
8
,9
1
incorporation.
Our previous approach via selective C–H
functionalize the arene, and electron-rich enough to provide high
selectivity in fluorination. For example, both DBT and B-DBT
salts of compound 25 could be synthesized in good yields.
However, fluorination of the B-DBT salt affords 94% yield of
desired fluorination product while DBT salt gives only 55% yield
of desired product with 42% yield of the undesired side-product
(see Supporting Information). By use of electron-rich M-DBT,
0
thianthrenation can also access aryl fluorides but requires an
iridium-catalyzed photoredox protocol, which adds additional
challenges for implementation at good manufacturing practice
1
1
(
GMP) production facilities in radiopharmacies. Here we report a
second highly selective arene C–H functionalization reaction,
which differs conceptually from thianthrenation in that it can
provide aryl sulfonium salts that can engage directly in C–F
bond formation, simply by addition of fluoride. Furthermore, we
1
8
F-fluorination with aryl sulfoniums can now proceed on
otherwise challenging electron-rich complex substrates (36, 38)
8
show how
a
group of three electronically different
(Table 2). Moreover, a range of small-molecule drugs were
1
8
18
dibenzothiophenes designed for F fluorination can markedly
expand the substrate scope compared to previous reported F-
fluorination of arylsulfoniums.
successfully F-labeled. Halides (30-32, 34, 35, 37), amides
1
8
(28), sulfonamides (31), heterocycles (33, 38) were well
tolerated. Substrates bearing ortho-substituents proceeded
8
18
efficiently to afford the desired F-labeled products (29, 30, 32,
7).
1
8
Essential for the success of a site-selective late-stage F-
labeling method is the availability of a practical and general
protocol to produce the precursors from readily available starting
materials. We found that, in the presence of acid anhydrides as
activators, reaction of bench-stable dibenzothiophene S-oxide
with ethylbenzene afforded the corresponding
dibenzothiophenium salt with high positional selectivity (p:o =
0:1; p:m = 100:1; Scheme 2). In contrast to previously reported
3
18
Table 2. Aromatic F-fluorination.
1
2
5
arylthianthrenium salts, aryl dibenzothiophenium salts can
provide aryl fluoride directly. For example, treatment of biphenyl-
derived dibenzothiophenium salt with fluoride afforded the aryl
fluoride in 84% isolated yield, yet the corresponding
thianthrenium salt gave the desired product in only 7% yield with
the wrong C–S cleavage product as the major side-product
(
Scheme 2). The site-selective C–H functionalization reaction
developed herein exhibits broad substrate scope (Table 1). Both
electron-poor (2, 21-23) and electron-rich arenes (16, 24, 27)
proceed efficiently with high regioselectivity. Various functional
groups are well tolerated, including halides (2, 21-24), nitriles (3),
ethers (4-5, 20), esters (4, 10, 15), ketones (5), aldehydes (7),
amides (5, 8, 25) and sulfonamides (9, 14). Heterocycles such
as quinolines (12), imidazoles (19), and pyridines (20) are also
compatible. Arenes that are more electron-deficient than 1,2-
dichlorobenzene are too electron-poor to react. The utility of our
method
for
site-selective
late-stage
aromatic
C–H
functionalization is further demonstrated by the reactions of
small complex substrates, drugs, agrochemicals and natural
products. For example, the dibenzothiophenium salt of
fenofibrate (10) was obtained in 89% isolated yield on gram
scale. For all the substrates shown in Table 1, analytically pure
compounds can be obtained by simple chromatography on silica
gel.
As depicted in Scheme 1, three differently substituted
dibenzothiophene S-oxides display similar high site-selectivity
under otherwise identical reaction conditions. For unsymmetrical
N
triaryl sulfonium salts, the S Ar reaction occurs preferentially at
(
a) Reaction conditions: aryl dibenzothiophenium precursor (9.0 µmol) in 500
8
,13
o
the most electron-deficient arene. , As such, an electron-rich
dibenzothiophen such as M-DBT should provide high selectivity
for the desired arene fluorination. However, M-DBT is less
reactive than more electron-deficient dibenzothiophenes such as
DBT, and cannot be used to efficiently C-H functionalize less
electron-rich arenes. Thus, the dibenzothiophene S-oxide
selected for each arene should be electron-deficient enough to
µL MeCN at 110 C for 20 min. RCY: decay-corrected radiochemical yield. (b)
Kryptofix 222 and K
DMSO.
2 3
CO were added, and reaction performed in 500 µL
1
8
Elution of the F-fluoride from the anion exchange cartridge is
1
4
commonly achieved with an aqueous solution of a base.
Aryldibenzothiophenium salts can be used directly for elution of
1
8
7g,i,l
F-fluoride, which avoids the addition of bases or kryptofix.
No special care is required to exclude air or moisture at any
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Angewandte Chemie International Edition
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COMMUNICATION
stage of the radio-synthesis, and the radiolabeled product can
be readily separated from the starting material due to the
pronounced polarity difference owing to the cationic sulfonium
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Keywords: C–F bond formation • site-selectivity • F-labeling •
radiochemistry • late-stage C–H functionalization
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COMMUNICATION
Entry for the Table of Contents
Layout 2:
COMMUNICATION
‡
‡
Peng Xu , Da Zhao , Florian Berger,
Aboubakr Hamad, Jens Rickmeier,
Roland Petzold, Mykhailo Kondratiuk,
Kostiantyn Bohdan, and Tobias Ritter *
Page No. – Page No.
Site-selective Late-Stage Aromatic
F-Fluorination via Aryl Sulfonium
Salts
1
8
A site-selective late-stage aromatic F-fluorination is reported. The collection of
18
1
8
three electronically different dibenzothiophenes enables F-labeling of a series of
small complex molecules.
This article is protected by copyright. All rights reserved.